Familial hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant inherited condition resulting in early onset parathyroid adenomas or hyperplasia, fibro-osseous jaw tumors, uterine adenofibromas or adenosarcomas, and occasionally, parathyroid carcinoma or Wils tumors. Discover and understanding of the genetic basis for this disease will provide opportunities for early diagnosis and treatment in affected families, as well as an understanding of sporadic tumors of these organs. We propose to identify and characterize that genetic basis. Our central hypothesis, backed by prior research, is that mutations of a single autosomal gene (HRPT2) cause all the manifestations of HPT-JT. To date, we have mapped HRPT-2 to a 22 cM region chromosome 1q25-q31 through genetic linkage analysis of 8 affected families. We have also identified ten potential tumor genes in this region. Our specific goals are to 1) further narrow this region, 2) determine if one of the ten candidate genes is HPRT1, and if one is, 3) characterize how the identified mutations affect the functioning of the gene product. If the ten fail, we will 4) search for new candidate genes by cDNA selection. More specifically, to narrow the region we will continue to use genetic linkage analysis and will expand our existing kindreds and seek as yet in discovered HPT-JT families. In addition, we will use LOH studies and incorporate more closely spaced markers in the region. Concurrently, we shall continue to map our ten candidate genes to specific YACs or BACs in the region, producing a map order for the given genes to approximately 1 Mb resolution. For candidate genes mapping to the refined HRPT2 region, we will determine which gene genes are expressed in tissues affected in HLP- JT and screen those genes for mutations using single-stranded conformation polymorphism analysis (SSCP) and sequencing. Once HRPT2 is identified, we will begin to characterize how the mutations in our families affect the functioning of the gene product. If no candidate genes actually map to the refined region, or if no apparently detrimental mutations are found in the mapped genes, we will search for HRPT2 through cDNA selection experiments. The strengths of our study include the unique clinical resource, the limited number of potential tumor-related candidate genes to evaluate, the collective experience and laboratory resources of our collaborative group, and our clearly-defined strategy for localizing this important new tumor gene.